DEVELOPMENT PROGRESS OF MESENCHYMAL STEM CELLS SENESCENCE_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHUHouyi , WANGFeng ,  WANGYuntao

Department of Spinal Surgery, Zhongda Hospital, Southeast University, Nanjing Jiangsu, 210009, P. R. China;

Corresponding author：

WANGYuntao, Email: wangyttod@seu.edu.cn

Keywords：

Mesenchymal stem cells; Senescence; Mechanism; Telomerase

DOI：

10.7507/1002-1892.20150193

Video：

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Objective To summarize the research situation of mesenchymal stem cells (MSCs) senescence, including the characteristics and mechanisms of senescence. Methods The original articles in recent years about MSCs senescence were extensively reviewed, and comprehensively analyzed. Results The senescence of MSCs which manifests as morphological senescence, reduced proliferation and differentiation potential, altered immunoregulation are found during the cultivation in experiment, which profoundly affects clinical application of MSCs. The research about the mechanisms of MSCs senescence includes telomere and telomerase, and stress-mediated injury etc, involving regulation of telomerase, and regulation of signal pathways of p53/p21, P13K/Akt, and Wnt/β-catenin etc. Conclusion The further study of senescence mechanisms will help to accelerate the clinical application of MSCs in the future.

Citation： ZHUHouyi, WANGFeng, WANGYuntao. DEVELOPMENT PROGRESS OF MESENCHYMAL STEM CELLS SENESCENCE. Chinese Journal of Reparative and Reconstructive Surgery, 2015, 29(7): 899-904. doi: 10.7507/1002-1892.20150193 Copy

1.	Yu KR,Kang KS.Aging-related genes in mesenchymal stem cells:a mini-review.Gerontology,2013,59(6):557-563.
2.	Wagner W,Wein F,Seckinger A,et al.Comparative characteristics of mesenchymal stem cells from human bone marrow,adipose tissue,and umbilical cord blood.Exp Hematol,2005,33(11):1402-1416.
3.	Redaelli S,Bentivegna A,Foudah D,et al.From cytogenomic to epigenomic profiles:monitoring the biologic behavior of in vitro cultured human bone marrow mesenchymal stem cells.Stem Cell Res Ther,2012,3(6):47.
4.	Janzen V,Forkert R,Fleming HE,et al.Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a.Nature,2006,443(7110):421-426.
5.	Bonab MM,Alimoghaddam K,Talebian F,et al.Aging of mesenchymal stem cell in vitro.BMC Cell Biol,2006,7:14.
6.	Jin HJ,Bae YK,Kim M,et al.Comparative analysis of human mesenchymal stem cells from bone marrow,adipose tissue,and umbilical cord blood as sources of cell therapy.Int J Mol Sci,2013,14(9):17986-18001.
7.	Muraglia A,Cancedda R,Quarto R.Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model.J Cell Sci,2000,113(Pt 7):1161-1166.
8.	Wang YQ,Wang M,Zhang P,et al.Effect of transplanted mesenchymal stem cells from rats of different ages on the improvement of heart function after acute myocardial infarction.Chin Med J (Engl),2008,121(22):2290-2298.
9.	Asumda FZ,Chase PB.Age-related changes in rat bone-marrow mesenchymal stem cell plasticity.BMC Cell Biol,2011,12:44.
10.	Mauney JR,Volloch V,Kaplan DL.Matrix-mediated retention of adipogenic differentiation potential by human adult bone marrow-derived mesenchymal stem cells during ex vivo expansion.Biomaterials,2005,26(31):6167-6175.
11.	Sethe S,Scutt A,Stolzing A.Aging of mesenchymal stem cells.Ageing Res Rev,2006,5(1):91-116.
12.	Baxter MA,Wynn RF,Jowitt SN,et al.Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.Stem Cells,2004,22(5):675-682.
13.	Lohmann M,Walenda G,Hemeda H,et al.Donor age of human platelet lysate affects proliferation and differentiation of mesenchymal stem cells.PLoS One,2012,7(5):e37839.
14.	Choudhery MS,Badowski M,Muise A,et al.Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation.J Transl Med,2014,12:8.
15.	Chen Y,Xu X,Tan Z,et al.Age-related BMAL1 change affects mouse bone marrow stromal cell proliferation and osteo-differentiation potential.Arch Med Sci,2012,8(1):30-38.
16.	Hwang SH,Park SH,Choi J,et al.Age-related characteristics of multipotent human nasal inferior turbinate-derived mesenchymal stem cells.PLoS One,2013,8(9):e74330.
17.	Lund TC,Kobs A,Blazar BR,et al.Mesenchymal stromal cells from donors varying widely in age are of equal cellular fitness after in vitro expansion under hypoxic conditions.Cytotherapy,2010,12(8):971-981.
18.	Zhu M,Kohan E,Bradley J,et al.The effect of age on osteogenic,adipogenic and proliferative potential of female adipose-derived stem cells.J Tissue Eng Regen Med,2009,3(4):290-301.
19.	Khan WS,Adesida AB,Tew SR,et al.The epitope characterisation and the osteogenic differentiation potential of human fat pad-derived stem cells is maintained with ageing in later life.Injury,2009,40(2):150-157.
20.	Stolzing A,Jones E,Mcgonagle D,et al.Age-related changes in human bone marrow-derived mesenchymal stem cells:consequences for cell therapies.Mech Ageing Dev,2008,129(3):163-173.
21.	Hardy R,Cooper MS.Bone loss in inflammatory disorders.J Endocrinol,2009,201(3):309-320.
22.	Fan Q,Tang T,Zhang X,et al.The role of CCAAT/enhancer binding protein (C/EBP)-alpha in osteogenesis of C3H10T1/2 cells induced by BMP-2.J Cell Mol Med,2009,13(8B):2489-2505.
23.	Despars G,Carbonneau CL,Bardeau P,et al.Loss of the osteogenic differentiation potential during senescence is limited to bone progenitor cells and is dependent on p53.PLoS One,2013,8(8):e73206.
24.	Liu TM,Ng WM,Tan HS,et al.Molecular basis of immortalization of human mesenchymal stem cells by combination of p53 knockdown and human telomerase reverse transcriptase overexpression.Stem Cells Dev,2013,22(2):268-278.
25.	Molchadsky A,Shats I,Goldfinger N,et al.p53 plays a role in mesenchymal differentiation programs,in a cell fate dependent manner.PLoS One,2008,3(11):e3707.
26.	韩燕,李栋,时庆,等.间充质干细胞的衰老对其免疫调控能力的影响.中国实验血液学杂志,2013,21(4):1010-1014.
27.	宁雪,李栋,汪大琨,等.脐带间充质干细胞体外衰老过程中生物学特性及基因表达谱的变化.中国实验血液学杂志,2012,20(2):458-465.
28.	Blackburn EH,Greider CW,Szostak JW.Telomeres and telomerase:the path from maize,Tetrahymena and yeast to human cancer and aging.Nat Med,2006,12(10):1133-1138.
29.	He L,Zheng Y,Wan Y,et al.A shorter telomere is the key factor in preventing cultured human mesenchymal stem cells from senescence escape.Histochem Cell Biol,2014,142(3):257-267.
30.	Yang C,Przyborski S,Cooke MJ,et al.A key role for telomerase reverse transcriptase unit in modulating human embryonic stem cell proliferation,cell cycle dynamics,and in vitro differentiation.Stem Cells,2008,26(4):850-863.
31.	Wang XY,Lan Y,He WY,et al.Identification of mesenchymal stem cells in aorta-gonad-mesonephros and yolk sac of human embryos.Blood,2008,111(4):2436-2443.
32.	Tsai CC,Chen CL,Liu HC,et al.Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines.J Biomed Sci,2010,17:64.
33.	Teng Y,Hu YY,Li XS,et al.Telomerase reverse transcriptase mediated immortalization of human bone marrow stromal cells.Brazilian Archives of Biology And Technology,2014,57(1):37-44.
34.	Cao H,Chu Y,Zhu H,et al.Characterization of immortalized mesenchymal stem cells derived from foetal porcine pancreas.Cell Prolif,2011,44(1):19-32.
35.	Burova E,Borodkina A,Shatrova A,et al.Sublethal oxidative stress induces the premature senescence of human mesenchymal stem cells derived from endometrium.Oxid Med Cell Longev,2013,2013:474931.
36.	Li S,Bian H,Liu Z,et al.Chlorogenic acid protects MSCs against oxidative stress by altering FOXO family genes and activating intrinsic pathway.Eur J Pharmacol,2012,674(2-3):65-72.
37.	Park KJ,Kim YJ,Kim J,et al.Protective effects of peroxiredoxin on hydrogen peroxide induced oxidative stress and apoptosis in cardiomyocytes.Korean Circ J,2012,42(1):23-32.
38.	Mimeault M,Batra SK.Recent insights into the molecular mechanisms involved in aging and the malignant transformation of adult stem/progenitor cells and their therapeutic implications.Ageing Res Rev,2009,8(2):94-112.
39.	Zhang DY,Wang HJ,Tan YZ.Wnt/beta-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway.PLoS One,2011,6(6):e21397.
40.	Brandl A,Meyer M,Bechmann V,et al.Oxidative stress induces senescence in human mesenchymal stem cells.Exp Cell Res,2011,317(11):1541-1547.
41.	Tsai CC,Chen YJ,Yew TL,et al.Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST.Blood,2011,117(2):459-469.
42.	Brandl A,Hartmann A,Bechmann V,et al.Oxidative stress induces senescence in chondrocytes.J Orthop Res,2011,29(7):1114-1120.
43.	Sperka T,Wang J,Rudolph KL.DNA damage checkpoints in stem cells,ageing and cancer.Nat Rev Mol Cell Biol,2012,13(9):579-590.
44.	王运涛,吴小涛,王锋,等.过早衰老髓核细胞微环境中BMSCs的生物学行为研究.中国修复重建外科杂志,2014,28(6):748-752.

1. Yu KR,Kang KS.Aging-related genes in mesenchymal stem cells:a mini-review.Gerontology,2013,59(6):557-563.
2. Wagner W,Wein F,Seckinger A,et al.Comparative characteristics of mesenchymal stem cells from human bone marrow,adipose tissue,and umbilical cord blood.Exp Hematol,2005,33(11):1402-1416.
3. Redaelli S,Bentivegna A,Foudah D,et al.From cytogenomic to epigenomic profiles:monitoring the biologic behavior of in vitro cultured human bone marrow mesenchymal stem cells.Stem Cell Res Ther,2012,3(6):47.
4. Janzen V,Forkert R,Fleming HE,et al.Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a.Nature,2006,443(7110):421-426.
5. Bonab MM,Alimoghaddam K,Talebian F,et al.Aging of mesenchymal stem cell in vitro.BMC Cell Biol,2006,7:14.
6. Jin HJ,Bae YK,Kim M,et al.Comparative analysis of human mesenchymal stem cells from bone marrow,adipose tissue,and umbilical cord blood as sources of cell therapy.Int J Mol Sci,2013,14(9):17986-18001.
7. Muraglia A,Cancedda R,Quarto R.Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model.J Cell Sci,2000,113(Pt 7):1161-1166.
8. Wang YQ,Wang M,Zhang P,et al.Effect of transplanted mesenchymal stem cells from rats of different ages on the improvement of heart function after acute myocardial infarction.Chin Med J (Engl),2008,121(22):2290-2298.
9. Asumda FZ,Chase PB.Age-related changes in rat bone-marrow mesenchymal stem cell plasticity.BMC Cell Biol,2011,12:44.
10. Mauney JR,Volloch V,Kaplan DL.Matrix-mediated retention of adipogenic differentiation potential by human adult bone marrow-derived mesenchymal stem cells during ex vivo expansion.Biomaterials,2005,26(31):6167-6175.
11. Sethe S,Scutt A,Stolzing A.Aging of mesenchymal stem cells.Ageing Res Rev,2006,5(1):91-116.
12. Baxter MA,Wynn RF,Jowitt SN,et al.Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.Stem Cells,2004,22(5):675-682.
13. Lohmann M,Walenda G,Hemeda H,et al.Donor age of human platelet lysate affects proliferation and differentiation of mesenchymal stem cells.PLoS One,2012,7(5):e37839.
14. Choudhery MS,Badowski M,Muise A,et al.Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation.J Transl Med,2014,12:8.
15. Chen Y,Xu X,Tan Z,et al.Age-related BMAL1 change affects mouse bone marrow stromal cell proliferation and osteo-differentiation potential.Arch Med Sci,2012,8(1):30-38.
16. Hwang SH,Park SH,Choi J,et al.Age-related characteristics of multipotent human nasal inferior turbinate-derived mesenchymal stem cells.PLoS One,2013,8(9):e74330.
17. Lund TC,Kobs A,Blazar BR,et al.Mesenchymal stromal cells from donors varying widely in age are of equal cellular fitness after in vitro expansion under hypoxic conditions.Cytotherapy,2010,12(8):971-981.
18. Zhu M,Kohan E,Bradley J,et al.The effect of age on osteogenic,adipogenic and proliferative potential of female adipose-derived stem cells.J Tissue Eng Regen Med,2009,3(4):290-301.
19. Khan WS,Adesida AB,Tew SR,et al.The epitope characterisation and the osteogenic differentiation potential of human fat pad-derived stem cells is maintained with ageing in later life.Injury,2009,40(2):150-157.
20. Stolzing A,Jones E,Mcgonagle D,et al.Age-related changes in human bone marrow-derived mesenchymal stem cells:consequences for cell therapies.Mech Ageing Dev,2008,129(3):163-173.
21. Hardy R,Cooper MS.Bone loss in inflammatory disorders.J Endocrinol,2009,201(3):309-320.
22. Fan Q,Tang T,Zhang X,et al.The role of CCAAT/enhancer binding protein (C/EBP)-alpha in osteogenesis of C3H10T1/2 cells induced by BMP-2.J Cell Mol Med,2009,13(8B):2489-2505.
23. Despars G,Carbonneau CL,Bardeau P,et al.Loss of the osteogenic differentiation potential during senescence is limited to bone progenitor cells and is dependent on p53.PLoS One,2013,8(8):e73206.
24. Liu TM,Ng WM,Tan HS,et al.Molecular basis of immortalization of human mesenchymal stem cells by combination of p53 knockdown and human telomerase reverse transcriptase overexpression.Stem Cells Dev,2013,22(2):268-278.
25. Molchadsky A,Shats I,Goldfinger N,et al.p53 plays a role in mesenchymal differentiation programs,in a cell fate dependent manner.PLoS One,2008,3(11):e3707.
26. 韩燕,李栋,时庆,等.间充质干细胞的衰老对其免疫调控能力的影响.中国实验血液学杂志,2013,21(4):1010-1014.
27. 宁雪,李栋,汪大琨,等.脐带间充质干细胞体外衰老过程中生物学特性及基因表达谱的变化.中国实验血液学杂志,2012,20(2):458-465.
28. Blackburn EH,Greider CW,Szostak JW.Telomeres and telomerase:the path from maize,Tetrahymena and yeast to human cancer and aging.Nat Med,2006,12(10):1133-1138.
29. He L,Zheng Y,Wan Y,et al.A shorter telomere is the key factor in preventing cultured human mesenchymal stem cells from senescence escape.Histochem Cell Biol,2014,142(3):257-267.
30. Yang C,Przyborski S,Cooke MJ,et al.A key role for telomerase reverse transcriptase unit in modulating human embryonic stem cell proliferation,cell cycle dynamics,and in vitro differentiation.Stem Cells,2008,26(4):850-863.
31. Wang XY,Lan Y,He WY,et al.Identification of mesenchymal stem cells in aorta-gonad-mesonephros and yolk sac of human embryos.Blood,2008,111(4):2436-2443.
32. Tsai CC,Chen CL,Liu HC,et al.Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines.J Biomed Sci,2010,17:64.
33. Teng Y,Hu YY,Li XS,et al.Telomerase reverse transcriptase mediated immortalization of human bone marrow stromal cells.Brazilian Archives of Biology And Technology,2014,57(1):37-44.
34. Cao H,Chu Y,Zhu H,et al.Characterization of immortalized mesenchymal stem cells derived from foetal porcine pancreas.Cell Prolif,2011,44(1):19-32.
35. Burova E,Borodkina A,Shatrova A,et al.Sublethal oxidative stress induces the premature senescence of human mesenchymal stem cells derived from endometrium.Oxid Med Cell Longev,2013,2013:474931.
36. Li S,Bian H,Liu Z,et al.Chlorogenic acid protects MSCs against oxidative stress by altering FOXO family genes and activating intrinsic pathway.Eur J Pharmacol,2012,674(2-3):65-72.
37. Park KJ,Kim YJ,Kim J,et al.Protective effects of peroxiredoxin on hydrogen peroxide induced oxidative stress and apoptosis in cardiomyocytes.Korean Circ J,2012,42(1):23-32.
38. Mimeault M,Batra SK.Recent insights into the molecular mechanisms involved in aging and the malignant transformation of adult stem/progenitor cells and their therapeutic implications.Ageing Res Rev,2009,8(2):94-112.
39. Zhang DY,Wang HJ,Tan YZ.Wnt/beta-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway.PLoS One,2011,6(6):e21397.
40. Brandl A,Meyer M,Bechmann V,et al.Oxidative stress induces senescence in human mesenchymal stem cells.Exp Cell Res,2011,317(11):1541-1547.
41. Tsai CC,Chen YJ,Yew TL,et al.Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST.Blood,2011,117(2):459-469.
42. Brandl A,Hartmann A,Bechmann V,et al.Oxidative stress induces senescence in chondrocytes.J Orthop Res,2011,29(7):1114-1120.
43. Sperka T,Wang J,Rudolph KL.DNA damage checkpoints in stem cells,ageing and cancer.Nat Rev Mol Cell Biol,2012,13(9):579-590.
44. 王运涛,吴小涛,王锋,等.过早衰老髓核细胞微环境中BMSCs的生物学行为研究.中国修复重建外科杂志,2014,28(6):748-752.

Chinese Journal of Reparative and Reconstructive Surgery

DEVELOPMENT PROGRESS OF MESENCHYMAL STEM CELLS SENESCENCE

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